Advertisement

Molecular and Chemical Neuropathology

, Volume 32, Issue 1–3, pp 101–121 | Cite as

Regulation of metallothionein-III (GIF) mRNA in the brain of patients with Alzheimer disease is not impaired

  • Marie-Claude Amoureux
  • Dominique Van Gool
  • Maria-Trinidad Herrero
  • René Dom
  • Francis C. Colpaert
  • Petrus J. Pauwels
Original Articles

Abstract

Contradictory results have been reported on the downregulation and role of the brain-specific protein metallothionein-III (MT-III, GIF) in Alzheimer disease (AD). In this article, the importance of MT-III downregulation in AD brain was re-evaluated in temporal and frontal cortex, hippocampus, and cerebellum of 11 AD patients and two groups of five and six control subjects, respectively. Reverse transcription-polymerase chain reaction (RT-PCR) was used to quantify the levels of MT-III mRNA relative to the levels of three constitutive RNAs: β-actin, glyceraldehyde-3-phosphate dehydrogenase (G3PHD), and ribosomal RNA 18S (rRNA 18S). The distribution of MT-III was similar to that of each of the three constitutive RNAs. The relative levels of each of these RNAs was high in brain regions examined in both AD patients and control subjects. Our findings do not support a downregulation of MT-III mRNA in the frontal cortex as well as the temporal cortex and hippocampus of AD patients. However, the level of MT-III mRNA was not constant in the investigated samples, suggesting that MT-III mRNA regulation could be controlled by factors other than AD pathology. Brain-derived neurotrophic factor (BDNF) mRNA levels were hardly detectable by RT-PCR in human brain tissue; a trend for a decrease was apparent in the temporal cortex of AD patients. In conclusion, the content of MT-III mRNA in the brain of AD patients was not detectably impaired, whereas BDNF mRNA may be affected.

Index Entries

Growth factor: metallothionein-III (GIF) BDNF RT-PCR human brain Alzheimer disease 

Abbreviations

AD

Alzheimer disease

AU

arbitrary units

BDNF

brain-derived neurotrophic factor

dNTP

deoxynucleotide triphosphate

EDTA

ethylenediaminetetraacetic acid

G3PDH

glyceraldehyde-3-phosphate dehydrogenase

GIF

growth inhibitory factor

MT-III

metallothionein-III

OD

optical density

PCR

polymerase chain reaction

rRNA 18S

ribosomal RNA 18S

RT

reverse transcription

SDS

sodium dodecyl sulfate

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Allen S. J., Macgowan S. H., Treanor J. J. S., Feeney R., Wilcock G. K., and Dawbarn D. (1991) Normal β-NGF content in Alzheimer's disease cerebral cortex and hippocampus.Neurosci. Lett. 131, 135–139.PubMedCrossRefGoogle Scholar
  2. Amoureux M-C., Wurch T., and Pauwels P. J. (1995) Modulation of Metallothionein-III mRNA content and growth rate of rat C6-glial cells by transfection with human 5-HT1D receptor genes.Biochem. Biophys. Res. Commun. 214, 639–645.PubMedCrossRefGoogle Scholar
  3. Appel S. H. (1981) A unifying hypothesis for the cause of amyotrophic lateral sclerosis, Parkinsonism, and Alzheimer disease.Ann. Neurol. 10, 499–505.PubMedCrossRefGoogle Scholar
  4. Arcari P., Martinelli R., and Salvatore F. (1984) The complete nucleotide sequence of a full length cDNA for human liver glyceraldehyde-3-phosphate dehydrogenase: evidence for multiple mRNA species.Nucleic Acids Res. 12, 9179–9189.PubMedCrossRefGoogle Scholar
  5. Arriagada P. V., Growdon J. H., Hedley Whyte E. T., and Hyman B. T. (1992) Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease.Neurology 42, 631–639.PubMedGoogle Scholar
  6. Barton A. J. L., Pearson R. C. A., Najlerahim A., and Harrisson P. J. (1993) Pre- and post-mortem influences on brain RNA.J. Neurochem. 61, 1–11.PubMedCrossRefGoogle Scholar
  7. Braak H. and Braak E. (1994) Pathology of Alzheimer's disease, inNeurodegenerative Diseases (Calne D. B., ed.), W. B. Saunders Company, Philadelphia, pp. 585–613.Google Scholar
  8. Crutcher K. A., Scott S. A., Liang S., Everson W. V., and Weingartner J. (1993) Detection of NGF-like activity in human brain tissue: increased levels in Alzheimer's disease.J. Neurosci. 13, 2540–2550.PubMedGoogle Scholar
  9. Erickson J. C., Sewell A. K., Jensen L. T., Winge D. R., and Palmiter R. D. (1994) Enhanced neurotrophic activity in Alzheimer's disease cortex is not associated with down regulation of metallothionein-III (GIF).Brain Res. 649, 297–304.PubMedCrossRefGoogle Scholar
  10. Goedert M., Fine A., Hunt S. P., and Ullrich A. (1986) Nerve growth factor mRNA in peripheral and central rat tissues and in the human central nervous system: Lesion effects in the rat brain and levels in Alzheimer's disease.Mol. Brain Res. 1, 85–92.CrossRefGoogle Scholar
  11. Goedert M., Fine A., Dawbarn D., Wilcock G. K., and Chao M. V. (1989) Nerve growth factor mRNA distribution in human brain: normal levels in basal forebrain in Alzheimer's disease.Mol. Brain Res. 5, 1–7.PubMedCrossRefGoogle Scholar
  12. Gomez-Pinilla F., Cummings B. J., and Cotman C. W. (1990) Induction of basic fibroblast growth factor in Alzheimer's disease pathology.NeuroReport 1, 211–214.PubMedCrossRefGoogle Scholar
  13. Gonzales I. L. and Schmickel R. D. (1986) The human 18S ribosomal RNA gene: evolution and stability.Am. J. Human Genet. 38, 419–427.Google Scholar
  14. Guillemette J. G., Wong L., McLachlan D. R., and Lewis P. N. (1986) Characterization of messenger RNA from the cerebral cortex of control and Alzheimer-affected brain.J. Neurochem. 47, 987–997.PubMedCrossRefGoogle Scholar
  15. Harrison P. J., Barton A. J. L., Najlerahim A., McDonald B., and Pearson R. C. A. (1991) Regional and neuronal reductions of polyadenylated messenger RNA in Alzheimer's disease.Psychol. Med. 21, 855–866.PubMedCrossRefGoogle Scholar
  16. Hefti F., Denton T. L., Knusel B., and Lapchak P. A. (1993) Neurotrophic factors: what are they and what are they doing? inNeurotrophic Factors (Loughlin S. E. and Fallon J. H., eds.), Academic, San Diego, CA, pp. 25–49.Google Scholar
  17. Holtzman D. H. and Mobley W. C. (1991) Molecular studies in Alzheimer's disease.Trends Biochem. Sci. 16, 140–144.PubMedCrossRefGoogle Scholar
  18. Hyman C., Hofer M., Barde Y. A., Juhask M., Yancoupoulos G. D., Squinto S. P., and Lindsay R. M. (1991) BDNF is a neurotrophic factor for dopaminergic neurons of the substantia nigra.Nature 350, 230–232.PubMedCrossRefGoogle Scholar
  19. Jetté N., Cole M. S., and Fahnestock M. (1994) NGF mRNA is not decreased in frontal cortex from Alzheimer's disease patients.Mol. Brain Res. 25, 242–250.PubMedCrossRefGoogle Scholar
  20. Knusel B., Winslow J. W., Rosenthal A., Burton L. E., Seid D. P., Nikolics K., and Hefti F. (1991) Promotion of central cholinergic and dopaminergic neuron differentiation by brain-derived neurotrophic factor but not neurotrophin-3.Proc. Natl. Acad. Sci. USA 88, 961–965.PubMedCrossRefGoogle Scholar
  21. Kobayashi H., Uchida Y., Ihara Y., Nakajima K., Kohsaka S., Miyatake T., and Tsuji S. (1993) Molecular cloning of rat growth inhibitory factor cDNA and the expression in the central nervous system.Mol. Brain Res. 9, 188–194.CrossRefGoogle Scholar
  22. Leibrock J., Lottspeich F., Hohn A., Hofer M., Hengerer B., Masiakowski P., Thoenen H., and Barde Y. A. (1989) Molecular cloning and expression of brain-derived neurotrophic factor.Nature 341, 149–152.PubMedCrossRefGoogle Scholar
  23. Marshak D. R., Pesce S. A., Stanley L. C., and Griffin W. S. (1992) Increased S-100 beta neurotrophic activity in Alzheimer's disease temporal lobe.Neurobiol. Aging 13, 1–7.PubMedCrossRefGoogle Scholar
  24. Masters B. A., Quaife C. J., Erickson J. C., Froelick G. J., Zambrowics B. P., Brinster R. L., and Palmiter R. D. (1995) Metallothionein-III is expressed in neurons that sequester zinc in synaptic vesicles.J. Neurosci. 14, 5844–5857.Google Scholar
  25. Murase K., Nabeshima T., Robitaille Y., Quirion R., Ogawa M., and Hayashi K. (1993) NGF level is not decreased in the serum, brain-spinal fluid, hippocampus, or parietal cortex of individuals with Alzheimer's disease.Biochem. Biophys. Res. Commun. 193, 198–203.PubMedCrossRefGoogle Scholar
  26. Murase K., Igasarashi K., and Hayashi K. (1994) Neurotrophin-3 (NT-3) levels in the developing rat nervous system and in human samples.Clin. Chim. Acta 227, 23–36.PubMedCrossRefGoogle Scholar
  27. Murray K. D., Gall C. M., Jones E. G., and Isackson P. J. (1994) Differential regulation of brain-derived neurotrophic factor and type II calcium/calmodulin-dependent protein kinase messenger RNA expression in Alzheimer's disease.Neuroscience 60, 37–48.PubMedCrossRefGoogle Scholar
  28. Palmiter R. D., Findley S. D., Whitmore T. E., and Durnam D. M. (1992) MTIII, a brain-specific member of the metallothionein gene family.Proc. Natl. Acad. Sci. USA 89, 6333–6337.PubMedCrossRefGoogle Scholar
  29. Pauwels P. J., Van Assouw H. P., De Ryck M., Leysen J. E., Dom R., and Van Gool D. (1993) Towards an improved survival of rat brain neurons in culture by cerebrospinal fluid of patients with senile dementia of Alzheimer's type.Brain Res. 610, 8–15.PubMedCrossRefGoogle Scholar
  30. Phillips H. S., Hains J. M., Armanini M., Laramee G. R., Johnson S. A., and Winslow J. W. (1991) BDNF mRNA is decreased in the hippocampus of individuals with Alzheimer's disease.Neuron 7, 695–702.PubMedCrossRefGoogle Scholar
  31. Ponte P., Ng S. Y., Engel J., Gunning P., and Kedes L. (1984) Evolutionary conservation in the untranslated regions of actin mRNAs: DNA sequence of a human beta-actin cDNA.Nucleic Acids Res. 12, 1687–1696.PubMedCrossRefGoogle Scholar
  32. Sheng J. G., Mrak R. E., and Griffin W. S. (1994) S-100 beta protein expression in Alzheimer disease: potential role in the pathogenesis of neuritic plaques.J. Neurosci. Res. 39, 398–404.PubMedCrossRefGoogle Scholar
  33. Spina M. B., Squinto S. P., Miller J., Lindsay R. M., and Hyman C. (1992) Brain-derived neurotrophic factor protects dopamine neurons against 6-hydroxydopamine and N-methyl-4-phenylpyridium ion toxicity: involvement of the glutathione system.J. Neurochem. 59, 99–106.PubMedCrossRefGoogle Scholar
  34. Stopa E. G., Gonzales A.-M., Chorsky R., Corona R. J., Alvarez J., Bird E. D., and Baird A. (1990) Basic fibroblast growth factor in Alzheimer's disease.Biochem. Biophys. Res. Commun. 171, 690–696.PubMedCrossRefGoogle Scholar
  35. Tabaton M., Mandybur T. I., Perry G., Onorato M., Autilio-Gambetti L., and Gambetti P. (1989) The widespread alteration of neurites in Alzheimer's disease may be unrelated to amyloid deposition.Ann. Neurol. 26, 771–778.PubMedCrossRefGoogle Scholar
  36. Terry R. D., Masliah E., and Hansen L. A. (1994) Structural basis of the cognitive alterations in Alzheimer disease, inAlzheimer Disease (Terry R. D., Katzman R., and Bick K. L., eds.), Raven, New York, pp. 179–196.Google Scholar
  37. Tsuji S., Kobayashi H., Uchida Y., Ihara Y., and Miyatake T. (1992) Molecular cloning of human growth inhibitory factor cDNA and its down-regulation in Alzheimer's disease.EMBO J. 11, 4843–4850.PubMedGoogle Scholar
  38. Uchida Y. (1994) Growth inhibitory factor, metallothionein-like protein and neurodegenerative diseases.Biol. Signals 3, 211–215.PubMedCrossRefGoogle Scholar
  39. Uchida Y. and Tomonaga M. (1989) Neurotrophic action of Alzheimer's brain extract is due to the loss of inhibitory factors for survival and neurite formation of cerebral cortical neurons.Brain Res. 481, 190–193.PubMedCrossRefGoogle Scholar
  40. Uchida Y., Ihara Y., and Tomonaga M. (1988) Alzheimer's disease brain extract stimulates the survival of cerebral cortical neurons from neonatal rats.Biochem. Biophys. Res. Commun. 150, 1263–1267.PubMedCrossRefGoogle Scholar
  41. Uchida Y., Takio K., Titani K., Ihara Y., and Tomonaga M. (1991) The growth inhibitory factor that is deficient in the Alzheimer's disease brain is a 68 amino acid metallothionein-like protein.Neuron 7, 337–347.PubMedCrossRefGoogle Scholar
  42. Van Eldik L. J. and Griffin W. S. (1994) S-100 beta protein expression in Alzheimer's disease: relation to neuropathology in brain regions.Biochim. Biophys. Acta 1223, 398–403.PubMedCrossRefGoogle Scholar
  43. Yugushi T., Kohmura E., Yamada K., Sakaki T., Yamashita T., Otsuki H., Wanaka A., Tohyama M., Tsuji S., and Hayakawa T. (1995) Changes in growth inhibitory factor mRNA expression compared with those of c-jun mRNA expression following facial nerve transection.Mol. Brain Res. 28, 181–185.CrossRefGoogle Scholar

Copyright information

© Humana Press Inc 1997

Authors and Affiliations

  • Marie-Claude Amoureux
    • 1
  • Dominique Van Gool
    • 2
  • Maria-Trinidad Herrero
    • 3
  • René Dom
    • 2
  • Francis C. Colpaert
    • 1
  • Petrus J. Pauwels
    • 1
  1. 1.Laboratory of Cellular and Molecular NeurobiologyCentre de Recherche Pierre FabreCastres CedexFrance
  2. 2.Department of NeuropathologyUniversity Hospital GasthuisbergLeuvenBelgium
  3. 3.Department of Anatomy, Faculty of MedicineUniversity of MurciaSpain

Personalised recommendations